Cinnamamidine derivatives



Patented Nov. 20, 1951 CINNAMAMIDINE DERIVATIVES Richard Baltzl'y, New York, and Emil Lorz,

Yonkers, N. Y., assignors toBurroughs Wellcome & 00. (U. S. A.) Inc., Tuckahoe, N. Y., a

corporation of New York No Drawing. Application March 24, 1949,

'- Serial No. 83,293

Claims (01. 260-564) The present invention relates to a new group of chemical compounds and more particularly to a new type of cinnamamidines which possess outstanding properties as local anesthetics in veterinary medicines. Some of the new compounds are particularly efiicient as surface anesthetics, while others have been found to be valuable as injection anesthetics. At least some of the new compounds are also believed to be suitablefor application in human medicine, but at present the clinical tests on these compounds have not been completed.

The new compounds are readily prepared in eX- cellent yield by the methods disclosed in our copending U. S. application Serial No. 700,366, filed October 1, 1946, and now abandoned, of which the present application is a continuation in part.

The physiologically active compounds according to the present invention are members of the group consisting of the unsubstituted N,N-dialkylcinnamamidines of the general formula:

in which R is an alkyl radical containing from two to six carbonatoms, and their ring substituted derivatives in which up to two carbon atoms in the ring are substituted by a radical selected from the group consisting of methoxy, ethoxy and methylene dioxy.

With regard to such local anesthetic potency the cinnamamidines according to the present invention show considerable variation in the type of action. N,N-di-n-butyl cinnamamidine is fourteen times as active as cocaine, tested on the guinea pig cornea, and thirteen times as active as procaine, tested by the guinea pig wheal method. These are both conventional testing procedures the former being designed to detect action as a surface anesthetic, the latter to discover activity in a substance for injection and anesthesia. The compound in question is about four times as toxic as cocaine, tested onmice. Substitution of methoxyl groups in the 3 and 4 positions makes the derived compound somewhat less toxic than cocaine, increases its activity as a surface anesthetic and largely abolishes its activityininjection anesthesia. 1" I In addition to this local anesthetic activity several of the substances according to the invention nature, provided it is not iself highly/toxic. Hy-

drochloric acid. hydrobromic acid. sulfuric acid. i

V phosphoric acid or organic acids such as malic acid, succinic acid, lactic acid or the like may be employed and any of these may ofler advantages in individual cases, but hitherto no other acid has been found preferable to hydrochloric acid. We therefore consider all non-toxic acids to be equivalent for this purpose and regard salts of this family of amidines with any such acid to be comprehended in the invention.

The following list of compounds, though not exhaustive, is believed to be representative of the physiologically active cinnamamidines according to the present invention:

1. N,N-di-n-butyl cinnamamidine.

2. N,N-diethy1-4-chlorocinnamamidine.

3. N,N-di-n-butyl-4-methoxy cinnamamidine.

4. N,N-di-sec butyl-z-methoxy cinnamamidine.

5. N,N-di-sec-butyl-4-ethoxy cinnamamidine.

6. N,N-di-n butyl-3,4-dimethoxy cinnamamidine.

7. N,N-di-n-propyl-3,4 diethoxy cinnamamidine.

8. N,N-di-n-butyl-2,5 -.dimethoxy cinnamamidine.

9. N,N-di-n-hexyl-2,3 dimethoxy cinnam'amidine.

10. N,N-di-n-hexy1-3,4-methylenedioxy cinnamamidine.

11. N,N-di-isopropyl-4-ethoxy-3-methoxy cinnamamidine.

12. N,N,-di-iso-butyl-2-ethoxy-3-methoxy cinnamamidine.

The compounds according to the present invention are conveniently prepared as described in our co-pending application Serial No. 700,366

,above mentioned, by the reaction of a halomagnesium dialkylamide with the appropriate nitrile.

The halomagnesium amide is formed by the addition of a secondary amine to a solution of a Grignard reagent, usually ethyl magnesium bromide. The preparation of the amidine therefore involves the following steps:

I @OlkdtLh-Nih R I H U 20' g. (0.15 mole) of di-n-butyl amine.

-layer was found to contain an oily base.

All three steps can be performed in one operation but there are practical advantages with this family of compounds in separating the third step as will be seen.

The general procedure is to prepare a solution of ethyl magnesium bromide at least equivalent to the quantity of nitrile to be used. There is then added a slight excess of the requisitesecondary amine, and the solution is refluxed 15-30 minutes to complete step (1) which is rapid but not instantaneous. The nitrile is then added at V a' rate such as to sustain gentle refluxing and the reaction mixture is refluxed for 1-4 hours.

If the solution, which now contains the halomagnesium derivative of the desired amidine, is poured into iced ammonium chloride solution :there is a precipitate, insoluble in water and ether, consisting of the bulk of the amidine in the form of a magnesium derivative. The precipitate can be filtered off and the product there- 'by largely separated from unreacted nitrile or secondary amine. Such behavior is not uncommon in amidine syntheses by our method but appears to be the rule with these cinnamamidines.

. The magnesium derivatives have not been in- 7 EXAMPLE 1 I I .N,N-di-n butyl cinnamamidine To a solution of ethylmagnesium bromide prepared from 3.7' g. (0.15 at.) of magnesium and 16.9 g. (0.15 mole) of ethyl bromide was added After the resultant solution had been refluxed 30 minutes there was added gradually 12.9 g. (0.1 mole) of cinnamonitrile. The reaction mixture was refluxed two hoursand poured into an excess of iced ammonium chloride solution. The bulk of the product separated as a colorless powder which was filtered off and Washed with Water and ether,

.The solid was then shaken with 5% sodium hydroxidesolutionand ether. The solid'dissolved,

magnesium hydroxide precipitated, and the ether The ethereal layer was dried over potassium carbonate and added to an excess of ethanolic hydrogen chloride solution. The amidine hydrochloride separated as colorless crystals which, after recrystallization from ethanol-ether mixture, melted at 204. By the same procedure 4-chlorocinnamonitrile was reacted with bromomagnesium diethylamide to give N,N-diethyl-4-chlorocinnamamidine. V

. EXAMPLE 2 N,N-dz'-n-butyl-4-methozcy cinnamamidine A Grignard solution was prepared from 2.1g.

(0.085 at.) of magnesium and 9.3 g. (0.085 mole) fluxed four hours and worked up by the method,

of Example 1. The hydrochloride of N,N -.di-n- 4 butyil-hmethoxy cinnamamidine melted at 214.

By the same method bromomagnesium-di-secbutyl amide reacted with 2-methoxy-cinnamoni- 'trile and with 4-ethoxy cinnamonitrile to give N,N- di-'sec-'butyl-2-methoxy-cinnamamidine and N,N-di-sec-butyl-i-ethoxy cinnamamidine.

EXAMPLE 3 N,N-din-butyl-3,4-dimethoxy cinnamamidine A solution of ethyl magnesium bromide was prepared from 2.5 g. (0.1 at.) of magnesium and 10.8 g. (0.1 mole) of ethyl bromide. added 12.9 g. (0.1 mole) of di-n-butylamine and the solution was refluxed 30 minutes, Ten g. (0.05 mole) :of 3,4-dimethoxy cinnamonitrile was admitted and the solution was refluxed three hours. After pouring into iced ammonium chloride solution the product was isolated by the method of Example 1. The N,N-di-n-butyl.3,-4- dimethoxy cinnamonitrile hydrochloride melted at -186" after crystallization from ethanolether mixture. 7

By the :same procedure 3,4-diethoxy cinnamo nitrile and bromomagnesium di-n-propyl amide yielded N,N-di-n-propyl-3,4-diethoxy cinnamamidine.

EXAMPLE 4 N,N-di-n-butyl-2,,5-dimethoxy cinnamamidine German-91am,

in which R is an alkyl radical containing from two to six carbon atoms, and their ring substituted derivativesin which up to two carbon atoms in the ring are substituted by a radical selected from. the group consisting of methoxy, ethoxy and methylene dioxy, and the water soluble salts of such cinnamamidine-s with non-toxic acids.

2. A compound selected from the class consisting of cinnamamidines of the type represented by the formula I NH in which R is an alkyl radical containing from two to six carbon atoms, and the water soluble salts of such cinnamamidines with non-toxic acids. 7

3'. A compound selected from the class consisting of cinnamamidines of'the type represented by the formula MeO To it was 5 salts of such cinnamamidines with non-toxic acids.

4. A compound selected from the class consisting of cinnamamidines of the type represented by the formula in which R is an alkyl radical containing from two to six carbon atoms, and the water soluble salts of such cinnamamidines with non-toxic acids.

5. A compound selected from the class consisting of N,N-.di-n-butyl cinnamamidine, and the water soluble salts thereof with non-toxic acids.

6. N,N-di-n-buty1 clnnamamidine hydrochloride.

7. A compound selected from the class consisting of N,N-di-n-butyl-4-methoxy cinnamamldine, and the water soluble salts thereof wtih nontoxic acids.

8. N,N-di-n-butyl-4-methoxy cinnamamidlne hydrochloride.

9. A compound selected from the class consisting of N,N-di-n-butyl-3,4-dimethoxy cinnamami- .dine, and the water soluble salts thereof with nontoxic acids.

10. N,N-di-n-butyl-3,4-dimethoxy cinnamamidine hydrochloride.

RICHARD BALTZLY. EMIL LORZ.

REFERENCES CITED UNITED STATES PATENTS Name Date Ziegler Aug. 4, 1936 OTHER REFERENCES Lorz et al., J. Am. Chem. Soc., vol. 70, pp. 1904 to 1907 (1948).

Number 

1. NEW CHEMICAL COMPOUNDS OF THE GROUP CONSISTING OF 